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Original Investigation
November 22, 2021

Time to Benefit of Bisphosphonate Therapy for the Prevention of Fractures Among Postmenopausal Women With Osteoporosis: A Meta-analysis of Randomized Clinical Trials

Author Affiliations
  • 1Division of Geriatrics, Department of Medicine, University of California, San Francisco
  • 2Geriatrics, Palliative and Extended Care Service Line, San Francisco Veterans Affairs Health Care System, San Francisco, California
JAMA Intern Med. Published online November 22, 2021. doi:10.1001/jamainternmed.2021.6745
Key Points

Question  What is the time to benefit of bisphosphonate therapy to prevent a nonvertebral fracture among postmenopausal women with osteoporosis?

Findings  In this meta-analysis of 10 randomized clinical trials involving 23 384 postmenopausal women with osteoporosis, 12.4 months was needed to avoid 1 nonvertebral fracture per 100 women who received bisphosphonate therapy.

Meaning  This study’s results suggest that bisphosphonate therapy is most likely to benefit postmenopausal women with osteoporosis who have a life expectancy greater than 12.4 months.

Abstract

Importance  The clinical decision to initiate bisphosphonate therapy for the treatment of osteoporosis requires balancing shorter-term harms and burdens (eg, gastroesophageal irritation or severe musculoskeletal pain) with longer-term benefits in reducing potential fractures.

Objective  To assess the time to benefit (TTB) of bisphosphonate therapy for the prevention of nonvertebral and other fractures among postmenopausal women with osteoporosis.

Data Sources  Randomized clinical trials (RCTs) were identified from systematic reviews commissioned by the US Preventive Services Task Force (1 review), the Agency for Healthcare Research and Quality (1 review), the Cochrane Library (2 reviews), and the Endocrine Society (1 review).

Study Selection  Studies selected were RCTs involving postmenopausal women with a diagnosis of osteoporosis based on existing vertebral fractures or bone mineral density T scores of −2.5 or lower. The selection process was focused on studies of alendronate, risedronate, and zoledronic acid because they are guideline-recommended first-line agents for reducing nonvertebral fractures. Studies were excluded if they did not focus on women with a primary diagnosis of osteoporosis, had no placebo arm, or had a lack of data on time to fracture.

Data Extraction and Synthesis  Random-effects Weibull survival curves were fitted and Markov chain Monte Carlo methods were used to estimate the absolute risk reduction (ARR) and TTB for each study. These estimates were pooled using a random-effects meta-analysis model.

Main Outcomes and Measures  The primary outcome was the time to 3 different ARR thresholds (0.002, 0.005, and 0.010) for the first nonvertebral fracture. Secondary outcomes included the time to 4 ARR thresholds (0.001, 0.002, 0.005, and 0.010) for hip fracture, any clinical fracture, and clinical vertebral fracture.

Results  Of 67 full-text articles identified, 10 RCTs comprising 23 384 postmenopausal women with osteoporosis were included either as the original RCT or part of subsequently published pooled analyses. Among the studies, the number of participants ranged from 994 to 7765, with mean (SD) age ranging from 63 (7) years to 74 (3) years and follow-up duration ranging from 12 to 48 months. The pooled meta-analysis found that 12.4 months (95% CI, 6.3-18.4 months) were needed to avoid 1 nonvertebral fracture per 100 postmenopausal women receiving bisphosphonate therapy at an ARR of 0.010. To prevent 1 hip fracture, 200 postmenopausal women with osteoporosis would need to receive bisphosphonate therapy for 20.3 months (95% CI, 11.0-29.7 months) at an ARR of 0.005. In addition, 200 postmenopausal women with osteoporosis would need to receive bisphosphonate therapy for 12.1 months (95% CI, 6.4-17.8 months) to avoid 1 clinical vertebral fracture at an ARR of 0.005.

Conclusions and Relevance  This meta-analysis found that the TTB of bisphosphonate therapy was 12.4 months to prevent 1 nonvertebral fracture per 100 postmenopausal women with osteoporosis. These results suggest that bisphosphonate therapy is most likely to benefit postmenopausal women with osteoporosis who have a life expectancy greater than 12.4 months.

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    1 Comment for this article
    THERAPEUTIC WINDOW -- missing dimensions
    Paul Nelson, MS, MD | Family Health Care, PC retired
    Given the unusually long half-life of alendronate (10 years), is there a point in time at which continued therapy with bisphosphonate therapy has no further fracture reducing benefit? And, is there a point in time where further therapy is more likely to result in complications?
    CONFLICT OF INTEREST: None Reported
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